Drugs, Neurochemistry and Transmission of Nervous Systems Flashcards
What are the fundamental principles of chemical neurotransmission at a synapse?
- Synthesis of NT
- Storage of NT
- Release of NT
- Reuptake of NT
- Metabolism of NT
- Receptor Interaction
What percentage of NA in synaptic clefts is reuptaken and recycled?
Approximatley 90-95% of synaptic NA is recycled - all most of it neuronally reuptaken and a small portion taken up extraneuronally (e.g. by glial cells)
NA regulatory feedback is achieved pre-synaptically via what type of receptor?
a2 adrenoceptors
What are monamine oxidases and catechol-o-methyltransferases (COMT)?
Monoamine Oxidases (MAO) are enzymes responsible for the breakdown of monoamines such as NA, Adr and dopamine. They are involved in the synaptic metabolism of recycled NA - mainly presynaptically but some extraneurally.
Catechol-o-methyltransferases (COMT) are enzymes that breakdown catecholamine such as dopamine, adrenaline and noradrenaline. They are involved in the synaptic metabolism of recycled NA - mainly extraneurally.
Describe the pathway of catecholamine biosynthesis
The only difference between cells capable of producing adrenaline from noradrenaline or dopamine is the presence of the later enzymes withint he pathway.
What are the dose dependent effects of cocaine?
- Intense euphoria + craving for more drug
- Psychological and physical dependence
* psychotic symptoms, depression, anxiety and fatigue - Cardiovascular effect
* hypertension, tachycardia, coronary vasospasm, dysrhythmia, convulsions
How do amphetamines and ephadrines affect NA storage in neurons?
Amphetamines and ephadrines are indirectly acting sympathomimetics that act on the presynaptic storage of NA.
These drugs displace NA from its storage vesicles. This results in the non-exocytotic release of NA into the synapse via catecholamine channels.
This causes increased activation of a- or b-adrenoceptors both peripherally and centrally.
What functions are noradrenergic and dopaminergic pathways associated with in the CNS?
Noradrenergic pathways are involved in stimulant, mood, appetite and cardiovascular regulation
Dopamine is considered nothing more than a precursor or NA in the periphery, but in the CNS dopaminergic pathways are involved in:
- Movement - Parkinson’s results from depletion of dopamine in basal ganglia
- Behaviour - Schizophrenia results from changes in dopamin rich areas
- Dependence - Dopaminergic neurons innervate known dependence nuclei in nucleus accumbens and ventral tegmental area
- Pituitary Function - Dopamin results in prolactin secretion
Discuss the selectivity of cocaine
Cocaine blocks the reuptake of noradrenaline, dopamine and serotonin at synapses in the CNS
The dopaminergic actions are linked to dependence.
Noradrenergic and serotonergic actions are leads for anti-depressant drugs in development.
What is the first line drug treatment of Parkinson’s Disease?
Parkinson’s Disease
Is characterised by the degeneration of dopaminergic pathways
Treatment with:
-
L-DOPA + peripheral DOPA Decarboxylase Inhibitor
- Increases the biosynthesis pathway of dopamine in the CNS; while mitigating peripheral side effects of dopamine in the periphery.
- Secondary: MAO B inhibitors, dopamine receptor agonists and muscarinci receptor antagonists
What is the first line drug treatment of Huntington’s Disease?
Huntington’s Disease
Is characterised by a deficiency in GABA within the CNS
Treatment:
- GABA agonist Baclofen
- Dopamine antagonists Chloropromazine
What are the three divisions of the autonomic nervous system?
- Sympathetic NS
- Parasympathetic NS
- Enteric NS
Do autonomic pathways originate in cervical or lower lumbar regions of the spinal cord?
No; there are no autonomic pathways arising from the cervical or lower lumbar enlargements
From which regions of the spinal cord do sympathetic and parasympathetic outputs arise respectively?
Sympathetic NS
Thoraco-lumbar spinal segments (but not lower lumbar)
Parasympathetic NS
Craniosacral spinal segments
Compare and contrast the position of sympathetic and parasympathetic ganglia
Sympathetic ganglia are typically located more distant to their organs of innervation. Most pre-ganglionic nerves of the sympathetic NS synapse to the paravertebral ganglia (sympathetic chain) that is parallel to the spinal column. These ganglia are the primary source of vasoconstrictor neurons.
Some preganglionic neurons, like pelvic visceral neurons, go through the paravertebral ganglia but do not synapse - instead synapsing on post-ganglionic neurons at **prevertebral ganglia **closer to organ of innervation.These ganglia are the primary source of non-vascular smooth muscle innervation.
Parasympathetic ganglia are generally located closer to or within individual organs.
Which level of neurons in the sympathetic, parasympathetic and somatic NS’s are myelinated?
All preganglionic nerves of the autonomic NS are lightly myelinated or unmyelinated.
Postganglionic nerves of the autonomic NS are all unmyelinated.
Somatic motor nerves are variable in myelination
Which neurotransmitters are considered ‘classical’ transmitters of the autonomic nervous system?
Provide examples of common ‘non-classical’ transmitters
Classical transmitters applies to the dominant neurotransmitters ACh and NA.
Non classical transmitters include:
- ATP
- Nitric Oxide
- Neuropeptides - Substance P, Neuropeptide Y
Often there is more than one transmitter being released at any one time = co-transmission.
Glutamate and GABA are not significant transmitters in the autonomic nervous system.
What is special about autonomic neurotransmission in the organs?
- No easily identifiable synaptic junctions
- More than 1 NT release site per axon
- Receptors can be expressed remotely from the synapse via extrajunctional receptors
Where in the spinal cord are preganglionic neurons located within the spinal cord?
Cholinergic preganglionic neurons of the sympathetic nervous system are located in the intermediolateral cell column of spinal cord grey matter.
With reference to the concepts of divergence and convergence, discuss the differences in post-ganglionic neurons in the sympathetic NS
Prevertebral ganglion neurons integrate more signals from multiple inputs (particularly the enteric nervous system) and have mor complex dendritic organise to allow greater convergence of information.
Up to 200 paravertebral ganglionic neurons can be activated by one preganglionic neuron - illustrating divergence to produce larger downstream effects.
What are the common functions of sympathetic nervous system activation?
Sympathetic activation is characterised by the ‘flight-or-flight’ set of responses; including:
- Increased heart rate
- Increased contractility of the heart
- Increased blood flow to skeletal muscle
- Decreased blood flow to gut
- Decreased gut motility
- Relaxation of airways
Additionally, the preganglionic sympathetics can activate the adrenal gland to release ACh and Adrenaline into the circulation and produce broad systemic activation of adrenoceptors throughout the body
Discuss some examples of preganglionic neurons of the parasympathetic NS that arise from the cranial compartment of the nervous system.
Edinger-Westfal Nucleus
Projects to the ciliary ganglion to control sphincter pupillae and ciliary muscle.
Salivatory Nuclei
To submandibular, sphenopalatine and optic ganglia to control lacrimal, salivary, sublingual, nasal and palatine glands
Dorsal Motor Nucleus of Vagus and Nucleus Ambiguss
To microganglia near and on outer surface of thoracic and abdominal organs for visceral functions
What is special about autonomic supply to the pelvic organs?
Autonomic supply to pelvic organs is via splanchnic nerves to pelvic ganglia that comprise the **pelvic plexus **overlying or within pelvic organs.
These parasympathetic ganglia have abnormally long axons - leaving them vulnerable to surgically induced injury.
These pelvic ganglia are mixed ganglia - also containing many sympathetic neurons.
Pelvic ganglia are mere relay stations - little integration/few dendrites present
Where in the spinal cord would you find cell bodies of preganglionic parasympathetic neurons?
Preganglionic parasympathetic neurons are located laterally within the intermediate grey zone of the sacral spinal cord
What are the common features of parasympathetic activation?
Parasympathetic activation invokes a ‘rest and digest’ set of functions; including:
- Decreased heart rate
- Decreased contractility of the heart
- Increased gut motility
- Constriction of airways
Compared with sympathetic pathways, parasympathetic have:
- lower ratios of pre:post ganglionic neurons (less divergence)
- Parasympathetic ganglia are simple relay stations that don’t integrate or coordinate information
- No equivalent of adrenal gland for systemic activation
How can you definitively distinguish between sympathetic and parasympathetic nerves?
The only unequivocal definition between sympathetic and parasympathetic nerves is the location of preganglionic fibres
Sympathetic: thoracic + lumbar spinal cord
Parasympathetic: cranial nuclei + sacral spinal cord
Other properties are unreliable and too many exceptions exist to be used as general rules of distinction; e.g.:
- Neurotransmitters
- Strucutre of ganglions neurons
- Physiological effects
Describe a typical autonomic reflex
Visceral afferent (sensory) neurons provide input to local interneurons and projection neurons (either ascending or efferent) within the spinal and brainstem circuits.
Most autonomic reflexes involve the brain (supraspinal reflex); rather than only the spinal cord(spinal reflex)
Lesions that disrupt ascending and descending connections with the brain can cause disruption to reflexes involving: bladder, sexual function, cardiovascular and thermal regulation
How is the hypothalamus involved in the coordination of autonomic output?
The hypothalamus initiates and coordinates an appropriate autonomic responses involving:
- Fight or flight
- Feeding
- Thermoregulation
- Circadian rhythms
- Water balance
- Sexual function
Hypothalamus compares current situations with biological set points; adjust behavoiur and autonomic function to achieve homeostasis.
It integrates with higher cortical and limbic systems to produce appropriate responses to emotion, fear, anxiety and motivations.
What is the role of the nucleus of the solitary tract in autonomic NS regulation?
The caudal part of the nucleus of the solitary tract (NTS) is located in the medulla.
It is a major integrative centre for autonomic function
It recieves input from visceral afferents and distributes information to either:
- local reflexes that control organ/tissue function via preganglionic neurons; or
- higher cortical and subcortical centres for more complex responses (e.g hypothalamus, thalamus and cortex)
What are local anaesthetics?
and
What classes of local anaesthetics exist?
Local anaesthetics are drugs that reversibly block the conduction of nerve impulses at the axonal membrane via Na+ channel inhibition
Local anaesthetics tend to be weak bases with different onset, duration and toxicity profiles
There are three main classes of local anaesthetics:
- Aminoesters
- Hydrophilic mechanism of action
- Shorter acting (30-45 min)
- Removed by hydrolysis via esterases
- e.g. procaine
- Aminoamides
- Hydrophilic mechanism of action
- Longer acting (hours)
- Removed via hepatic metabolism
- e.g. Lignocaine and **Ropivicaine **(most common in Aus)
-
Benzocaine
* Hydrophobic mechanism of action
Where is the binding site of local anaesthetics?
Local anaesthetics bind S6 in transmembrane domain IV of Na+ channels
- This binding site is intracellular - affects the mechanism of action of local anaesthetics able to enter the cell
- Hydrophobic (benzocaine) vs Hydrophilic (aminoester and aminoamines)
Toxins (tetrodotoxin/puffer fish) bind extracellular domains of Na+ channels to cause anaesthetic action - different mode
Discuss the differences in sensitivity to local anaesthetics between different types of nerves.
Smaller nerve fibres are more sensitive to local anaesthetic effects. Thus sensitivity in:
sensory > autonomic > motor
The preferential effects on sensory nerves allows sensation to be inhibited without compromising the motor effects of the nervous system - e.g respiratory and cardiac innervation required for survival.
In sufficient concentrations, however, widespread motor impairment is likely.
Compare the two different mechanisms of local anaesthetic action
There are two mechanisms of local anaesthetic actions:
Hydrophobic Pathway (non use-dependent)
The base form of the drug (B) is the predominant form (uncharged) and freely diffuses through the lipid membrane of axons as a hydrophobic molecule. It directly binds to the S6 transmembrane domain and blocks electrical conduction.
This pathway is fast acting and non-use-dependent due to the rapid ease of binding. Benzocaine is an example
Hydrophilic Pathway (use dependent)
The predominant drug form is ionised (BH+) and has difficulty in diffusing through axon membrane. Small proportion is in base form (B) and this is able to diffuse through into the intracellular space. In the intracellular space base form (B) becomes charged again (BH+) and enters the channel to bind S6 - this requires the channels to be open and being ‘used’.
Thus, they are slow acting and use dependent. Examples include aminoesters and aminoamines.
What is the difference between primary and secondary forms of hyperalgesia and allodynnia?
What factors are considered when determining the type (short acting vs long acting) of benzodiazepine?
clue: use as a hypnotic or anxiolytic?
Why are benzodiazepines safer when overdosing compared to barbituates?
The direct gating or opening of the chloride ion channel is the reason for the increased toxicity of barbiturates compared to benzodiazepines in
overdose.
Benzodiazepines increase the frequency of the chloride ion channel opening at the GABA-A receptor. As an allosteric modulator of the receptor, there is a functional ceiling of effect that benzodiaepines reach -> unable to produce more effect/harm above this level.
Illustrate the progression in anti-depressant development throughout recent history
